Drug abuse is a chronic relapse mental disorder that affects millions of people. However, there are few effective treatments and the outlook for new ones is not promising because of the poor understanding of the causes of addiction. In recent years, several novel genes and proteins have been described that may have a role in drug addiction and merit consideration for study. CART (Cocaine and Amphetamine-Regulated Transcript) peptides are a family of neuropeptides whose function in the brain is poorly understood but are thought to be important to the motivation and in the addictive properties of stimulants such as cocaine and amphetamine. This proposal will test the hypothesis that CART peptides modulate the rewarding properties of stimulants such as cocaine and amphetamine. CART peptides are thought to enhance the neural coding for reward associated with stimulants. Although CART peptides are best known for their ability to suppress food intake -- a classic feature of stimulants, they were initially identified by us because cocaine and amphetamine increase its expression of its gene in the rat nucleus accumbens, a brain area associated with motivation. The distribution of CART and CART peptides in neural circuitry of motivation is unique among chemical transmitters and receptors. Our recent studies show that CART knockout (KO) mice exhibit decreased locomotor responses to amphetamine compared to wild-type mice. A recent report shows that CART peptides produce conditioned place preference in rats. These and other data suggest that the rewarding property of stimulants is regulated by CART peptides. The role of CART peptides in the rewarding properties of stimulants will be tested three ways. First, a series of CART peptides, some of which are novel, will be produced by expression in heterologous cells. Second, the stimulatory and conditioning properties of these CART peptides as well as endogenous ones will be tested by measuring their effects on locomotor activity and conditioned place preference in rats. Third, the effects of cocaine and amphetamine as well as CART peptides on CART KO mice will be investigated at a behavioral, cellular and molecular level. These studies will determine whether CART peptides modulate the rewarding properties of stimulants. CART peptides may be possible substrates of stimulant addiction, and as such, they represent a novel therapeutic target. Selective CART peptide pharmacotherapies for stimulant addiction may be successful because these peptides show a restricted distribution in brain, and as neuropeptides, they have modulatory functions in chemical signaling. These medications may also find use in the treatment of obesity and eating related disorders. Hence, this work has implications for the biology and treatment of drug addiction, but also for food related disorders.